This invention relates to new aryloxy indole derivatives as pharmaceuticals which are useful for the treatment in mammals of diseases affected by disorders of the serotonin-affected neurological systems, such as depression, anxiety, panic disorder, obsessive-compulsive disorder, sleep disorders, sexual dysfunction, bipolar disorders, psychosis, stress-related disorders, including post-traumatic stress disorders, Tourettes"" syndrome, attention deficit disorder, with and without hyperactivity, alcohol and drug addiction, Alzheimer""s disease, Parkinson""s disease, obesity and acute and chronic pain, including migraine pain, as well as methods of enhancing cognition.
EP 0714894 A1 discloses the preparation of compounds of formula II as new 5-HT1f agonist for the treatment of migraine headaches. EP 429341 A2 claims compounds of formula III as having serotonin transporter activity. A recent publication by Malleron et al. was also reported based around formula I [J. Med. Chem. 36, 1194 (1993)]. EP 722941 A2 discloses compounds having effects on serotonin-related systems of formula IV. 
Pharmaceuticals which enhance serotonergic neurotransmission are of useful benefit for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin (5-HT) reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism per se cannot account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of 5-HT neuron, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. Recent studies by Artigas et al. (Trends Neurosci., 1996, 19, 378-383) suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concomitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
The compounds of this invention are aryloxy piperidinyl indoles represented by Formula I: 
wherein:
R1 is hydrogen or alkyl of from 1 to 6 carbon atoms;
R2, R3, and R4 are each independently selected from hydrogen, alkyl of from 1 to 6 carbon atoms, or halogen;
X is selected from hydrogen, halogen, CN, or C1-C6 alkoxy;
Z is (CH2)n or carbonyl;
n is 1 or 2; and
the dashed line indicates an optional double bond;
or a pharmaceutically acceptable salt thereof.
One group of compounds of this invention comprises those of the formula: 
wherein:
X is selected from hydrogen, halogen, CN, or C1-C6 alkoxy;
R1 is hydrogen or alkyl of from 1 to 3 carbon atoms; and
R2, R3, and R4 are each independently selected from hydrogen, alkyl of from 1 to 6 carbon atoms, or halogen;
or a pharmaceutically acceptable salt thereof.
Another group of compounds of this invention comprise those of the formula: 
wherein:
X is selected from hydrogen, halogen, CN, or C1-C6 alkoxy;
R1 is hydrogen or alkyl of from 1 to 3 carbon atoms; and
R2, R3, and R4 are each independently selected from hydrogen, alkyl of from 1 to 6 carbon atoms, or halogen;
or a pharmaceutically acceptable salt thereof.
The compounds of this Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of Formula I are generally prepared by the overall sequence indicated in Scheme 1 as follows: 
The following examples for preparation of intermediates and invention compounds are included for illustrative purposes and are not to be construed as limiting to this disclosure in any way. Those skilled in the art of organic synthesis may be aware of still other synthetic routes to the invention compounds. The reagents and intermediates used herein are either commercially available or prepared according to standard literature procedures.
(5-Fluoro-1H-indol-3-yl)-pyridin-4-yl-methanol. To a stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol (10.0 mL) was added 4-pyridinecarboxaldehyde (2.20 mL, 23.0 mmol), followed by addition of NaOH (2.5 mL, 50%) at 0xc2x0 C. After stirring for 1 h at 0xc2x0 C., the reaction mixture was warmed to room temperature and stirred for 3 h, followed by the addition of water (10.0 mL). The precipitate was collected by filtration and dried under vacuum to afford 5.2 g (93%) of a light yellow solid: mp 171-173xc2x0 C.; 1H NMR (DMSO, 400 MHz), 5.85 (d, 1H), 5.93 (d, 1H), 6.86-7.34 (m, 4H), 7.43 (dd, 2H), 8.48 (dd, 2H), 11.09 (br s, 1H); MS (El) m/z 242 (M+); HRMS calcd for C14H12FN2O [M+H] 243.09337, found 243.09576.
5-Fluoro-3-[(4-pyridinyl)methyl]-1H-indole. To a suspension of (5-fluoro-1H-indol-3-yl)-pyridin-4-yl-methanol (0.799 g, 3.3 mmol) in methylene chloride (13 mL) was added triethylsilane (0.60 mL, 3.7 mmol) followed by trifluoroacetic acid (2.85 mL, 37 mmol) at room temperature. After addition of trifluoroacetic acid, a clear black solution was obtained. The reaction mixture was stirred overnight and the solvent and excess trifluoroacetic acid was removed on a rotary evaporator. To the residue was added saturated Na2CO3 to adjust the pH greater than 9. The aqueous layer was extracted with methylene chloride and the combined organic extracts was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride to methylene chloride/ethyl acetate to ethyl acetate, 100% to 50% to 100%) to give 0.56 g (75%) of a solid: mp 141-142xc2x0 C. [(mp 149xc2x0 C.; previously reported in J. Med. Chem. 36,1194 (1993)].
5-Fluoro-3-[(4-piperidinly)methyl]-1 H-indole. This compound was prepared from intermediate 2 in 88% yield following the reported procedure (Malleron et.al, J. Med. Chem. 1993, 36, 1194).
(4a) 2-(1H-Indol-4-yloxy)-chloroethane: This compound was prepared from 5-hydroxyindole and chloroethanol in 57% using Mitsunobu conditions as reported in the literature (Mewshaw et al. J. Med. Chem. 1999, 42, 2007); mp 62-63xc2x0 C.; 1H NMR (CDCl3) 3.88 (2H, t, J=6.2 Hz), 4.38 (2H, t, J=6.2 Hz), 6.52 (1H, d, J=7.3 Hz), 6.68 (1H, app. t, J=2.2 Hz), 7.02-7.12 (3H, m), 8.14 (1H, s).
(4b) 2-Methyl-2-(1H-indol-4-yloxy)-chloroethane was similarly prepared as described above as a yellow oil: (47%); MS (El) 209 (M+).